chr5-90781548-G-A

Position:

• chr5-90781548-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000405460.9(ADGRV1):​c.13201G>A​(p.Glu4401Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,458,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E4401E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ADGRV1 ENST00000405460.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.36

Genes affected

ADGRV1 (HGNC:17416): (adhesion G protein-coupled receptor V1) This gene encodes a member of the G-protein coupled receptor superfamily. The encoded protein contains a 7-transmembrane receptor domain, binds calcium and is expressed in the central nervous system. Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. Several alternatively spliced transcripts have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.13201G>A	p.Glu4401Lys	missense_variant	65/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.13201G>A	p.Glu4401Lys	missense_variant	65/90	1	NM_032119.4	ENSP00000384582	P1
ADGRV1	ENST00000638510.1	n.468G>A		non_coding_transcript_exon_variant	1/26	1
ADGRV1	ENST00000425867.3	c.2155G>A	p.Glu719Lys	missense_variant	13/38	5		ENSP00000392618
ADGRV1	ENST00000639431.1	c.265+105339G>A		intron_variant, NMD_transcript_variant		5		ENSP00000491057

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1458464 Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 6 AN XY: 725132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000991

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 18, 2015

The p.Glu4401Lys variant in GPR98 has not been previously reported in individual s with hearing loss or Usher syndrome or in large population studies. Computatio nal prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of t he p.Glu4401Lys variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 228708). This variant has not been reported in the literature in individuals affected with ADGRV1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 4401 of the ADGRV1 protein (p.Glu4401Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Benign	-0.71	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	.;N;.
REVEL	Benign	0.22
Sift	Uncertain	0.020	.;D;.
Sift4G	Uncertain	0.011	.;D;.
Polyphen		0.99	D;D;.
Vest4		0.88
MutPred		0.62		Gain of methylation at E4401 (P = 0.0071);Gain of methylation at E4401 (P = 0.0071);.;
MVP		0.75
MPC		0.29
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.46
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876657819; hg19: chr5-90077365;